Niemann-Pick Disease, Type C
Conditions
Keywords
NPC1, Niemann-Pick Type C, Niemann-Pick, arimoclomol, lysosomal storage disorder, lysosomal storage disease, NPC2, NP-C
Brief summary
A prospective, randomized, double-blind, placebo controlled therapeutic study in participants with confirmed diagnosis of Niemann-Pick disease type C (NPC). The purpose of this study is to assess the efficacy and safety of arimoclomol (compared to placebo) when it is administered as an add-on therapy to the participant's current prescribed best routine clinical care; participant's routine clinical care may, or may not, include miglustat. The CT-ORZY-NPC-002 study has been expanded to include an open label paediatric sub-study including participants aged 6 to \<24 months at study enrolment.
Detailed description
A prospective, randomized, double-blind, placebo controlled therapeutic study in participants with confirmed diagnosis of Niemann-Pick disease type C (NPC). Participants must either 1) have completed Visit 2 (end of study \[EOS\]) of the CT-ORZY-NPC-001 study or 2) meet the eligibility criteria of this study including a requirement of stable treatment with miglustat for 6 months (if on miglustat therapy) prior to enrolment into the study. Aim: The purpose of this study is to assess the efficacy and safety of arimoclomol (compared to placebo) when it is administered as an add-on therapy to the participant's current prescribed best routine clinical care; participant's routine clinical care may, or may not, include miglustat. Randomization: Participants will be randomized to receive placebo or arimoclomol (with an allocation ratio of 1:2). Pharmacokinetic evaluation (age below 12): To confirm the selected dose, participants less than 12 years of age will undergo an arimoclomol single-dose pharmacokinetic (PK) evaluation before randomization and the start of continuous (multiple dosing) treatment. Early Escape Clause: In participants whose disease progression is too severe and/or too fast, the early escape clause will allow the Investigator to apply the escape route which implies that the participant can be treated with arimoclomol (as per blinded phase study schedule) and be followed up according to the study schedule or until the analysis of data from the controlled, 12-month blinded phase study period does not support the efficacy and/or safety of arimoclomol. Study duration: The duration of the blinded phase study period will be 12-months. Following this, all participants will be offered to continue into the extension phase of the study where every participant will receive arimoclomol and be followed up and attend site visits every 6 months until 60 months after randomization. The extension phase runs until arimoclomol has received Regulatory Approval or until the analysis of data from the controlled, blinded phase 12-month study period does not support the efficacy and/or safety of arimoclomol. The CT-ORZY-NPC-002 protocol has been updated to include a paediatric sub-study including new and naïve participants aged 6 to \<24 months at study enrolment. Aim: The purpose of the paediatric sub-study, is to assess the safety and tolerability of 36 months of open-label arimoclomol when administered as an add-on therapy to the participant's current prescribed best routine clinical care; participant's routine clinical care may, or may not, include miglustat. The Paediatric sub-study will run at the open sites participating in the main study. A total of 3-5 participants are planned to be enrolled. All participants will be treated with arimoclomol. Main Inclusion Criteria: * Diagnosis of NPC1 or NPC2; * NPC diagnosis confirmed by: * Genetically confirmed (deoxyribonucleic acid \[DNA\] sequence analysis) by mutations in both alleles of NPC1 or NPC2, OR * Mutation in only one allele of NPC1 or NPC2 plus either positive filipin staining or elevated cholestane triol/oxysterols (\>2 x upper limit of normal). * Males and females aged 6 to \<24 months, with a cap of maximum 3 participants above 18 months * Treated or not treated with miglustat; * If a participant is on prescribed treatment with miglustat, the dose must have been stable for at least 1 month prior to inclusion in the paediatric sub-study * If a participant has been discontinued from prescribed treatment with miglustat, they must have been discontinued for at least 1 month prior to inclusion in the paediatric sub-study * The Legal Authorised Representative (LAR) has read and signed the Informed Consent Form (ICF) prior to any study-related procedures * The LAR agrees for the participant to participate in all aspects of the trial design Main Exclusion Criteria: * Recipient of a liver transplant or a planned liver transplant * The Aspartate Transaminase (AST) and/or Alanine Transaminase (ALT) \>3 x Upper Limit of Normal (ULN) for age and gender * Renal insufficiency with serum creatinine level \>1.5 x ULN * Participants with known causes of active liver disease or prolonged icterus or malformation of organs other than NPC * Participant was born before 37 weeks of gestation * Participant weight \<5 kg at study enrollment * Participant is diagnosed with severe intra-uterine growth restriction * Participant has severe neurological symptoms * Participant has received or plans to receive a bone marrow transplant Arms and Intervention: 1 arm open label treatment with arimoclomol capsules 100 mg (dispersed in water) for oral administration (3 times daily). Doses: The dose in mL is based on the participant's weight in kg. Randomization: Open Label Pharmacokinetic: To confirm the selected dose, participants will undergo an arimoclomol single-dose pharmacokinetic (PK) evaluation before the start of continuous treatment. Visit schedule time frame: Screening (V1); enrollment Week 1 (V2 baseline), Weeks 2 (V3), continuing visits at months 1 (V4), 3 (V5), 6 (V6), 9 (V7), 12 (V8), 15 (V8a), 18 (V9), 24 (V10), 30 (V11) and 36 (V12). Primary objective: Safety and tolerability Main Endpoint measures: Safety data: Adverse events (AEs); Vital signs; Hematology; Clinical chemistry Clinical status data: Clinical signs and symptoms captured through physical examination; Change from baseline in patient weight and height; Change in Bayley III score: Developmental delay scoring Imaging data: Changes from baseline in the size of the liver and spleen assessed by ultrasound
Interventions
DRUGarimoclomol
DRUGPlacebo
Sponsors
ZevraDenmark
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
EITHER NP-C participants who have entered the CT-ORZY-NPC-001 study and who have completed Visit 2 (EOS) of the CT-ORZY-NPC-001 study. OR NPC participants who did not enter or complete the CT-ORZY-NPC-001 study but are fulfilling all of criteria listed below: ◦Diagnosis of NPC1 or NPC2; NPC diagnosis confirmed by: * Genetically confirmed (deoxyribonucleic acid \[DNA\] sequence analysis) by mutations in both alleles of NPC1 or NPC2, OR * Mutation in only one allele of NPC1 or NPC2 plus either positive filipin staining or elevated cholestane triol/oxysterols (\>2 x upper limit of normal). * Males and females aged from 2 years to 18 years and 11 months; * Treated or not treated with miglustat; * If a participant is under prescribed treatment with miglustat, it has to be under stable dose of the medication for at least 6 continuous months prior to inclusion in the CT-ORZY-NPC-002 study; o If a participant has been discontinued from prescribed treatment with miglustat, they must have been discontinued for at least 3 continuous months prior to inclusion in the CT-ORZY-NPC-002 study; * Body mass index (BMI) Z score ≥ -2 SD (standard deviation) for age, according to the World Health Organisation (WHO) standards; * Presenting at least one neurological symptom of the disease (for example, but not limited to, hearing loss, vertical supranuclear gaze palsy, ataxia, dementia, dystonia, seizures, dysarthria, or dysphagia); * Ability to walk either independently or with assistance. * Written informed consent (and assent if appropriate to local laws and regulations) prior to any study-related procedures; * Willing to participate in all aspects of trial design including blood sampling (PK, blood biomarkers and safety labs), skin biopsies and imaging (ultrasonography of the liver and spleen); * Ability to travel to the corresponding clinical trial site at the scheduled visit times for evaluation and follow-up; * All sexually active female participants of child-bearing potential (post-menarchal) must use highly effective contraception during the study and until 1 week after the last dose of IMP. Highly effective birth control methods include: Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; and vasectomised partner. All sexually active male participants with female partners of child-bearing potential (post-menarchal) must use a condom with or without spermicide in addition to the birth control used by their partners during the study and until 3 months after the last dose of IMP. Sexual abstinence is considered a highly effective birth control method only if it is defined as refraining from heterosexual intercourse during the study and for 1 week after the last dose of IMP (for female participants of child-bearing potential) and for 3 months after the last dose of IMP (for male participants with female partners of child-bearing potential). The reliability of sexual abstinence needs to be evaluated by the Investigator in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. •Ability to comply with the protocol-specified procedures/evaluations and scheduled visits.
Exclusion criteria
* Recipient of a liver transplant or planned liver transplantation; * Severe liver insufficiency (defined as hepatic laboratory parameters, AST and/or ALT greater than three-times the upper limit of normal for age and gender (central laboratory assessment); * Renal insufficiency, with serum creatinine level greater than 1.5 times the upper limit of normal (central laboratory assessment); * Known or suspected allergy or intolerance to the IMP (arimoclomol or constituents); * In the opinion of the Investigator, the participant's clinical condition does not allow for the required blood collection and/or skin biopsies as per the protocol-specified procedures; * Treatment with any investigational drug during the study or in the 4 weeks prior to entering the study. This includes treatment with any investigational drug during the study in an attempt to treat NP-C; * Pregnancy or breastfeeding; * Current participation in another trial is not permitted unless it is a non-interventional study and the sole purpose of the trial is for long-term follow up/survival data (registry); * For participants who have not completed the CT-ORZY-NPC-001 study, fulfilling any of the criteria listed below: * Participants with uncontrolled severe epileptic seizures period (at least 3 consecutive severe epileptic seizures that required medication) within 2 months prior to the written consent. This includes participants with ongoing seizures that are not stable in frequency or type or duration over a 2 month period prior to enrolment, requiring change in dose of antiepileptic medication (other than adjustment for weight) over a 2 month period prior to enrolment, or requiring 3 or more antiepileptic medications to control seizures; * Neurologically asymptomatic participants; * Severe manifestations of NP-C disease that would interfere with the participant's ability to comply with the requirements of this protocol; * Treatment with any IMP within 4 weeks prior to the study enrolment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Scores | Baseline to Month 12 | NPC disease severity was assessed based on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders in 5-domain NPCCSS - Defined as Participants Where the 5-domain NPCCSS Score Remains Stable or Improves as Compared to Baseline | Baseline to Month 12 | NPC disease severity was assessed based on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. Stable was defined as a participant's total score for the 5 domains being the same at month 12 as at baseline. Improvement was defined as a participant's total score at month 12 being lower than at baseline. |
| Time to Worsening | Baseline to Month 12 | Time to worsening was defined as the time until the participant reached the predefined minimal clinically important difference (MCID) of 2 points compared to baseline on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. The values reported per group are the 25th percentile Kaplan-Meier estimates and 95% confidence interval. |
| Percentage of Participants With Worsening | Months 6 and 12 | Worsening was defined as participants that have reached the predefined MCID of 2 points on their 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. |
| Change From Baseline in 17-domain NPCCSS Apart From Hearing Domains (i.e. Hearing and Auditory Brainstem Response) | Baseline to 6 and 12 months | The NPC Clinical Severity Scale (NPCCSS) is a disease-specific, clinician-reported outcome measure developed to characterize and quantify NPC disease progression. The 17-domain NPCCSS includes clinical signs and symptoms in nine major and eight minor domains, which are rated on scales of 0-5 (for the major domains) or 0-2 (for the minor domains). The total score is the sum of the score of each of the 17 domains and ranges from 0 to 61, with a high score indicating a more severe clinical impairment. |
| Change From Baseline in 5-domain NPCCSS Score | Baseline to 6 months | The 5-domain NPC Clinical Severity Scale (NPCCSS) focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. |
| Changes From Baseline in Each Individual Domain of the NPCCSS | Baseline to 6 and 12 months | The NPC Clinical Severity Scale (NPCCSS) is a disease-specific, clinician-reported outcome measure developed to characterize and quantify disease progression. The 17-domain NPCCSS includes clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, swallowing,) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems) domains, which are rated on scales of 0-5 (for the major domains) or 0-2 (for the minor domains). A higher score indicates a more severe clinical impairment. |
| Percentage of Responders in Clinical Global Impression Scale of Improvement (CGI-I) - Defined as Percentage of Participants Where the CGI-I Score Remains Stable or Shows Improvement (This Outcome Measure Was Considered Co-primary by the FDA) | Month 12 | The CGI-I is a 7-point scale that rates total improvement of participant's condition. The clinician rates the participants from 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, or 7=Very much worse. Scores thus range from 1-7 with lower scores indicating greater improvement. Responders were the participants with a score of 1 or 2 at Month 12. |
| Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y) | Baseline to 6 and 12 months | The EQ-5D-Y descriptive system includes 5 descriptive items: Mobility, self-care, doing usual activities, having pain or discomfort, and feeling anxiety or depressed. Each dimension has 3 levels: No problems, some problems, and a lot of problems. The change in the 5 individual items of the EQ-5D-Y per participant was explored by using the pareto principle at 6 and 12 months to show the number (%) of participants who felt: * Better (better on at least one dimension and no worse in any other dimension), * Worse (worse in at least one dimension, and no better in any other dimension) |
| Change From Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score | Baseline to 6 and 12 months | The SARA included eight items reflecting neurologic manifestations of cerebellar ataxia. The test provides a direct and simple description of motor function in a participant. The test consists of 8 test items: gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movements, and heel-shin slide. The total score of the 8 items ranges from 0 (normal cerebellar function) to 40 (not able to perform any of the test items). |
| Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT) | Baseline to 6 and 12 months | The 9HPT test is a direct and simple measurement of fine motor coordination function, eye/hand coordination, and the ability to follow a simple direction. The 9HPT is a timed test in which nine pegs are inserted and removed from nine holes in the pegboard. Both hands are tested starting with the dominant hand. The time spent in completing the 9 HPT using each hand was recorded. |
| Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Months 6 and 12 | The CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment. A rating of 1 is considered normal, or with the least severe symptoms, a rating of 7 is extremely ill, or the worst symptoms. Scores thus range from 1-7 with lower scores indicating less severe disease. |
| Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Months 6 and 12 | The CGI-I is a 7-point scale that rates total improvement of participant's condition. The clinician rates the participants from 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, or 7=Very much worse. Scores thus range from 1-7 with lower scores indicating greater improvement. |
| Change From Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified Stampfer Score) | Baseline to 6 and 12 months | The NPC Clinical Database (NPC-cdb) score aims to reflect the current clinical status of the participant. The NPC-cdb score represents both historical symptoms and a current status. The test consists of ten areas: visceral signs, development, motor function, ocular-motor abnormalities, seizures/cataplexy/narcolepsy, cognitive abilities and memory, behavioral and psychiatric abnormalities, speech, hearing, and abilities in daily life. The current status score is a severity-weighted sum of 72 symptoms considered as disease-relevant at the time of assessment. Each symptom contributes with a score between 1 and 5, the maximum score is 125. An increase in score reflects a reduction in the participant's abilities. |
Countries
Denmark, France, Germany, Italy, Poland, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 14 sites in Denmark, France, Germany, Italy, Poland, Spain, Switzerland, United Kingdom, and United States.
Pre-assignment details
To confirm the selected dose of arimoclomol for participants less than 12 years of age, the 28 participants below 12 years old received a single arimoclomol dose for PK evaluation before randomization and the start of continuous treatment. A total of 50 participants were randomized in the blinded phase (continuous dose phase) and the study is ongoing in an open-label period.
Participants by arm
| Arm | Count |
|---|---|
| Arimoclomol (12-month Double-blind Phase) Participants received arimoclomol capsules, orally based on participant's body weight, TID for 12 months. | 34 |
| Placebo (12-month Double-blind Phase) Participants received matching placebo to arimoclomol capsules, orally based on participant's body weight, TID for 12 months. | 16 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Continuous Treatment Period | Death | 0 | 1 | 0 |
| Continuous Treatment Period | Early Escape | 0 | 2 | 0 |
| Continuous Treatment Period | Participant Meets Criteria for IMP Administration to be Stopped and Subsequent Withdrawal | 0 | 0 | 1 |
| Continuous Treatment Period | Participant's Parents/legal guardian have Withdrawn Informed Consent | 0 | 1 | 0 |
| Continuous Treatment Period | Safety Reasons | 0 | 3 | 0 |
| Single Dose Treatment Period | Screening Failure | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo (12-month Double-blind Phase) | Arimoclomol (12-month Double-blind Phase) |
|---|---|---|---|
| 17-domain NPCCSS Except Hearing Domains | 19.9 score on a scale STANDARD_DEVIATION 11.4 | 17.2 score on a scale STANDARD_DEVIATION 11.3 | 21.2 score on a scale STANDARD_DEVIATION 11.5 |
| 5-domain Niemann-Pick Disease Type C Clinical Severity Scale (NPCCSS) Score | 11.2 score on a scale STANDARD_DEVIATION 6.8 | 9.4 score on a scale STANDARD_DEVIATION 6.4 | 12.1 score on a scale STANDARD_DEVIATION 6.9 |
| Age at Diagnosis of First Neurological Symptom | 5.10 years STANDARD_DEVIATION 3.54 | 5.22 years STANDARD_DEVIATION 3.87 | 5.05 years STANDARD_DEVIATION 3.43 |
| Age, Continuous | 11.1 years STANDARD_DEVIATION 5 | 10.2 years STANDARD_DEVIATION 4.1 | 11.5 years STANDARD_DEVIATION 5.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 16 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Participants Currently Treated With Miglustat No | 11 Participants | 3 Participants | 8 Participants |
| Participants Currently Treated With Miglustat Yes | 39 Participants | 13 Participants | 26 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 45 Participants | 13 Participants | 32 Participants |
| Sex: Female, Male Female | 26 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Male | 24 Participants | 7 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 1 / 34 | 0 / 16 |
| other Total, other adverse events | 4 / 28 | 30 / 34 | 13 / 16 |
| serious Total, serious adverse events | 2 / 28 | 5 / 34 | 6 / 16 |
Outcome results
Primary
Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Scores
NPC disease severity was assessed based on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment.
Time frame: Baseline to Month 12
Population: Full Analysis Set (FAS) included those participants who were randomized and who had received at least one dose of randomized treatment medication. Overall Number analyzed is the number of participants evaluated at a specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Scores | 0.76 score on a scale |
| Placebo (12-month Double-blind Phase) | Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Scores | 2.15 score on a scale |
Comparison: A general linear mixed model (GLMM) for repeated measurements was used for the analysis of NPC disease severity assessed based on the 5-domain NPCCSS scores at Month 12. The general linear mixed model analysis for repeated measures was fitted with treatment, miglustat level and visit as fixed effects including treatment-by-visit interaction and baseline score as a covariate.p-value: 0.045695% CI: [-2.76, -0.03]GLMM for Repeated Measures
Secondary
Change From Baseline in 17-domain NPCCSS Apart From Hearing Domains (i.e. Hearing and Auditory Brainstem Response)
The NPC Clinical Severity Scale (NPCCSS) is a disease-specific, clinician-reported outcome measure developed to characterize and quantify NPC disease progression. The 17-domain NPCCSS includes clinical signs and symptoms in nine major and eight minor domains, which are rated on scales of 0-5 (for the major domains) or 0-2 (for the minor domains). The total score is the sum of the score of each of the 17 domains and ranges from 0 to 61, with a high score indicating a more severe clinical impairment.
Time frame: Baseline to 6 and 12 months
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication. Here, Number analyzed signifies number of participants evaluated at specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in 17-domain NPCCSS Apart From Hearing Domains (i.e. Hearing and Auditory Brainstem Response) | Change at Month 6 | 0.53 score on a scale |
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in 17-domain NPCCSS Apart From Hearing Domains (i.e. Hearing and Auditory Brainstem Response) | Change at Month 12 | 1.20 score on a scale |
| Placebo (12-month Double-blind Phase) | Change From Baseline in 17-domain NPCCSS Apart From Hearing Domains (i.e. Hearing and Auditory Brainstem Response) | Change at Month 6 | 2.22 score on a scale |
| Placebo (12-month Double-blind Phase) | Change From Baseline in 17-domain NPCCSS Apart From Hearing Domains (i.e. Hearing and Auditory Brainstem Response) | Change at Month 12 | 2.81 score on a scale |
Comparison: Change From Baseline in 17-Domain NPCCSS Apart from Hearing Domains (i.e. Hearing and Auditory Brainstem Response) at Month 6 was analyzed using the Analysis of covariance (ANCOVA) model. ANCOVA model was fitted with treatment, baseline full-scale NPCCSS apart from hearing domains score, and use of miglustat as covariates.p-value: 0.154695% CI: [-4.04, 0.66]ANCOVA
Comparison: Change From Baseline in 17-Domain NPCCSS Apart from Hearing Domains (i.e. Hearing and Auditory Brainstem Response) at Month 12 was analyzed using the ANCOVA model. ANCOVA model is fitted with treatment, baseline full-scale NPCCSS apart from hearing domains score, and use of miglustat as covariates.p-value: 0.219995% CI: [-4.24, 1.01]ANCOVA
Secondary
Change From Baseline in 5-domain NPCCSS Score
The 5-domain NPC Clinical Severity Scale (NPCCSS) focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment.
Time frame: Baseline to 6 months
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in 5-domain NPCCSS Score | 0.48 score on a scale |
| Placebo (12-month Double-blind Phase) | Change From Baseline in 5-domain NPCCSS Score | 1.60 score on a scale |
Comparison: An ANCOVA model was fitted with treatment, baseline 5-domain NPCCSS score, and use of miglustat as covariates.p-value: 0.018895% CI: [-2.03, -0.19]ANCOVA
Secondary
Change From Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified Stampfer Score)
The NPC Clinical Database (NPC-cdb) score aims to reflect the current clinical status of the participant. The NPC-cdb score represents both historical symptoms and a current status. The test consists of ten areas: visceral signs, development, motor function, ocular-motor abnormalities, seizures/cataplexy/narcolepsy, cognitive abilities and memory, behavioral and psychiatric abnormalities, speech, hearing, and abilities in daily life. The current status score is a severity-weighted sum of 72 symptoms considered as disease-relevant at the time of assessment. Each symptom contributes with a score between 1 and 5, the maximum score is 125. An increase in score reflects a reduction in the participant's abilities.
Time frame: Baseline to 6 and 12 months
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified Stampfer Score) | Change at Month 6 | -0.38 score on a scale |
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified Stampfer Score) | Change at Month 12 | 1.85 score on a scale |
| Placebo (12-month Double-blind Phase) | Change From Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified Stampfer Score) | Change at Month 6 | 4.71 score on a scale |
| Placebo (12-month Double-blind Phase) | Change From Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified Stampfer Score) | Change at Month 12 | 4.88 score on a scale |
Comparison: Change from baseline in the NPC-CDB score (modified Stampfer Score) at Month 6 was analyzed using the ANCOVA model. ANCOVA model was fitted with treatment, baseline NPC-CDB total score and use of miglustat as covariates.p-value: 0.053695% CI: [-10.26, 0.08]ANCOVA
Comparison: Change from baseline in the NPC-CDB score (modified Stampfer Score) at Month 12 was analyzed using the ANCOVA model. ANCOVA model was fitted with treatment, baseline NPC-CDB total score and use of miglustat as covariates.p-value: 0.378595% CI: [-9.9, 3.85]ANCOVA
Secondary
Change From Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score
The SARA included eight items reflecting neurologic manifestations of cerebellar ataxia. The test provides a direct and simple description of motor function in a participant. The test consists of 8 test items: gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movements, and heel-shin slide. The total score of the 8 items ranges from 0 (normal cerebellar function) to 40 (not able to perform any of the test items).
Time frame: Baseline to 6 and 12 months
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score | Change at 6 months | 0.79 score on a scale |
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score | Change at 12 months | 1.06 score on a scale |
| Placebo (12-month Double-blind Phase) | Change From Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score | Change at 6 months | 0.05 score on a scale |
| Placebo (12-month Double-blind Phase) | Change From Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score | Change at 12 months | 0.78 score on a scale |
Comparison: Change from baseline in the SARA score at Month 6 was measured using an ANCOVA model. ANCOVA model was fitted with treatment, baseline SARA score, and use of miglustat as covariates.p-value: 0.37195% CI: [-0.92, 2.4]ANCOVA
Comparison: Change from baseline in the SARA score at Month 12 was measured using an ANCOVA model. ANCOVA model was fitted with treatment, baseline SARA score and use of miglustat as covariates.p-value: 0.789995% CI: [-1.82, 2.37]ANCOVA
Secondary
Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT)
The 9HPT test is a direct and simple measurement of fine motor coordination function, eye/hand coordination, and the ability to follow a simple direction. The 9HPT is a timed test in which nine pegs are inserted and removed from nine holes in the pegboard. Both hands are tested starting with the dominant hand. The time spent in completing the 9 HPT using each hand was recorded.
Time frame: Baseline to 6 and 12 months
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT) | Dominant Hand: Change at 6 months | 1.54 seconds |
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT) | Non-dominant Hand: Change at 6 months | 0.60 seconds |
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT) | Dominant Hand: Change at 12 months | -3.29 seconds |
| Arimoclomol (12-month Double-blind Phase) | Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT) | Non-dominant Hand: Change at 12 months | 11.68 seconds |
| Placebo (12-month Double-blind Phase) | Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT) | Non-dominant Hand: Change at 12 months | 17.59 seconds |
| Placebo (12-month Double-blind Phase) | Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT) | Dominant Hand: Change at 6 months | 11.88 seconds |
| Placebo (12-month Double-blind Phase) | Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT) | Dominant Hand: Change at 12 months | -6.49 seconds |
| Placebo (12-month Double-blind Phase) | Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT) | Non-dominant Hand: Change at 6 months | 16.46 seconds |
Comparison: Dominant Hand: Change From Baseline in the Nine-Hole Peg Test (9HPT) at Month 6 was measured using an ANCOVA model: ANCOVA models were fitted with treatment, baseline dominant/non-dominant hand 9HPT time (secs), and use of miglustat as covariatesp-value: 0.619595% CI: [-53.01, 32.33]ANCOVA
Comparison: Non-dominant Hand: Change From Baseline in the Nine-Hole Peg Test (9HPT) at Month 6 was measured using an ANCOVA model: ANCOVA models were fitted with treatment, baseline dominant/non-dominant hand 9HPT time (secs), and use of miglustat as covariatesp-value: 0.469395% CI: [-60.73, 29]ANCOVA
Comparison: Dominant Hand: Change From Baseline in the Nine-Hole Peg Test (9HPT) at Month 12 was measured using an ANCOVA model: ANCOVA models were fitted with treatment, baseline dominant/non-dominant hand 9HPT time (secs), and use of miglustat as covariatesp-value: 0.728395% CI: [-15.71, 22.12]ANCOVA
Comparison: Non-dominant Hand: Change From Baseline in the Nine-Hole Peg Test (9HPT) at Month 12 was measured using an ANCOVA model: ANCOVA models were fitted with treatment, baseline dominant/non-dominant hand 9HPT time (secs), and use of miglustat as covariatesp-value: 0.770895% CI: [-47.54, 35.72]ANCOVA
Secondary
Changes From Baseline in Each Individual Domain of the NPCCSS
The NPC Clinical Severity Scale (NPCCSS) is a disease-specific, clinician-reported outcome measure developed to characterize and quantify disease progression. The 17-domain NPCCSS includes clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, swallowing,) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems) domains, which are rated on scales of 0-5 (for the major domains) or 0-2 (for the minor domains). A higher score indicates a more severe clinical impairment.
Time frame: Baseline to 6 and 12 months
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication. Here, Number analyzed signifies number of participants evaluated at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Cognition: Change at Month 6 | 0.2 score on a scale | Standard Deviation 0.5 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hearing: Change at Month 12 | 0.0 score on a scale | Standard Deviation 0 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Swallow: Change at Month 6 | 0.1 score on a scale | Standard Deviation 1.1 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Auditory Brainstem Response: Baseline | 0.2 score on a scale | Standard Deviation 0.4 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Cognition: Change at Month 12 | 0.3 score on a scale | Standard Deviation 0.6 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Auditory Brainstem Response: Change at Month 6 | 0.0 score on a scale | Standard Deviation 0 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Speech: Change at Month 6 | 0.1 score on a scale | Standard Deviation 0.5 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Auditory Brainstem Response: Change at Month 12 | 0.0 score on a scale | Standard Deviation 0 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Eye Movement: Baseline | 2.2 score on a scale | Standard Deviation 1.2 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Behavior: Baseline | 0.4 score on a scale | Standard Deviation 0.6 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Swallow: Change at Month 12 | 0.1 score on a scale | Standard Deviation 1.1 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Behavior: Change at Month 6 | 0.0 score on a scale | Standard Deviation 0.5 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Eye Movement: Change at Month 6 | 0.0 score on a scale | Standard Deviation 0.6 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Behavior: Change at Month 12 | 0.1 score on a scale | Standard Deviation 0.6 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Ambulation: Change at Month 6 | 0.1 score on a scale | Standard Deviation 0.4 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Gelastic Cataplexy: Baseline | 0.8 score on a scale | Standard Deviation 0.9 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Eye Movement: Change at Month 12 | 0.2 score on a scale | Standard Deviation 0.9 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Gelastic Cataplexy: Change at Month 6 | 0.1 score on a scale | Standard Deviation 0.5 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Fine Motor Skills: Baseline | 2.8 score on a scale | Standard Deviation 1.8 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Gelastic Cataplexy: Change at Month 12 | 0.2 score on a scale | Standard Deviation 0.6 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Memory: Baseline | 1.9 score on a scale | Standard Deviation 1.4 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hyperreflexia: Baseline | 1.0 score on a scale | Standard Deviation 0.7 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Speech: Change at Month 12 | -0.2 score on a scale | Standard Deviation 1 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hyperreflexia: Change at Month 6 | -0.0 score on a scale | Standard Deviation 0.5 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Memory: Change at Month 6 | 0.1 score on a scale | Standard Deviation 0.5 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hyperreflexia: Change at Month 12 | 0.1 score on a scale | Standard Deviation 0.7 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Fine Motor Skills: Change at Month 6 | 0.1 score on a scale | Standard Deviation 0.7 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Incontinence: Baseline | 1.0 score on a scale | Standard Deviation 0.8 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Memory: Change at Month 12 | 0.1 score on a scale | Standard Deviation 0.5 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Incontinence: Change at Month 6 | -0.1 score on a scale | Standard Deviation 0.4 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Speech: Baseline | 2.2 score on a scale | Standard Deviation 1.6 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Incontinence: Change at Month 12 | -0.0 score on a scale | Standard Deviation 0.4 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Seizures: Baseline | 1.9 score on a scale | Standard Deviation 1.9 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Narcolepsy (NARCO): Baseline | 0.1 score on a scale | Standard Deviation 0.4 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Fine Motor Skills: Change at Month 12 | 0.2 score on a scale | Standard Deviation 0.8 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Narcolepsy (NARCO): Change at Month 6 | 0.0 score on a scale | Standard Deviation 0.4 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Seizures: Change at Month 6 | -0.1 score on a scale | Standard Deviation 0.8 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Narcolepsy (NARCO): Change at Month 12 | -0.1 score on a scale | Standard Deviation 0.4 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Swallow: Baseline | 1.9 score on a scale | Standard Deviation 1.7 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Psychiatric: Baseline | 0.1 score on a scale | Standard Deviation 0.4 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Seizures: Change at Month 12 | 0.3 score on a scale | Standard Deviation 0.8 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Psychiatric: Change at Month 6 | -0.0 score on a scale | Standard Deviation 0.3 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Cognition: Baseline | 2.8 score on a scale | Standard Deviation 1.3 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Psychiatric: Change at Month 12 | 0.0 score on a scale | Standard Deviation 0.3 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hearing: Baseline | 0.4 score on a scale | Standard Deviation 1 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Respiratory: Baseline | 0.1 score on a scale | Standard Deviation 0.3 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Ambulation: Change at Month 12 | 0.3 score on a scale | Standard Deviation 0.5 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Respiratory: Change at Month 6 | 0.0 score on a scale | Standard Deviation 0.5 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hearing: Change at Month 6 | -0.2 score on a scale | Standard Deviation 0.8 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Respiratory: Change at Month 12 | 0.1 score on a scale | Standard Deviation 0.5 |
| Arimoclomol (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Ambulation: Baseline | 2.5 score on a scale | Standard Deviation 1.6 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Respiratory: Change at Month 12 | 0.2 score on a scale | Standard Deviation 0.4 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Ambulation: Baseline | 2.2 score on a scale | Standard Deviation 1.6 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Ambulation: Change at Month 6 | 0.3 score on a scale | Standard Deviation 1 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Ambulation: Change at Month 12 | 0.3 score on a scale | Standard Deviation 0.9 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Speech: Baseline | 1.6 score on a scale | Standard Deviation 1.2 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Speech: Change at Month 6 | 0.1 score on a scale | Standard Deviation 0.3 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Speech: Change at Month 12 | 0.3 score on a scale | Standard Deviation 0.8 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Swallow: Baseline | 1.3 score on a scale | Standard Deviation 1.7 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Swallow: Change at Month 6 | 0.4 score on a scale | Standard Deviation 1 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Swallow: Change at Month 12 | 0.6 score on a scale | Standard Deviation 1 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Fine Motor Skills: Baseline | 1.9 score on a scale | Standard Deviation 1.8 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Fine Motor Skills: Change at Month 6 | 0.5 score on a scale | Standard Deviation 1.1 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Fine Motor Skills: Change at Month 12 | 0.6 score on a scale | Standard Deviation 1.3 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Cognition: Baseline | 2.5 score on a scale | Standard Deviation 1.5 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Cognition: Change at Month 6 | 0.3 score on a scale | Standard Deviation 0.8 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Cognition: Change at Month 12 | 0.1 score on a scale | Standard Deviation 0.6 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Eye Movement: Baseline | 2.1 score on a scale | Standard Deviation 1.1 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Eye Movement: Change at Month 6 | -0.1 score on a scale | Standard Deviation 0.7 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Eye Movement: Change at Month 12 | -0.1 score on a scale | Standard Deviation 0.6 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Memory: Baseline | 1.3 score on a scale | Standard Deviation 1.5 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Memory: Change at Month 6 | 0.2 score on a scale | Standard Deviation 1.1 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Memory: Change at Month 12 | 0.3 score on a scale | Standard Deviation 0.8 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Seizures: Baseline | 1.3 score on a scale | Standard Deviation 1.8 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Seizures: Change at Month 6 | 0.0 score on a scale | Standard Deviation 1.5 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Seizures: Change at Month 12 | -0.1 score on a scale | Standard Deviation 1.7 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hearing: Baseline | 0.0 score on a scale | Standard Deviation 0 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hearing: Change at Month 6 | 0.0 score on a scale | Standard Deviation 0 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hearing: Change at Month 12 | 0.3 score on a scale | Standard Deviation 0.8 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Auditory Brainstem Response: Baseline | 0.1 score on a scale | Standard Deviation 0.4 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Auditory Brainstem Response: Change at Month 6 | 0.2 score on a scale | Standard Deviation 0.4 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Auditory Brainstem Response: Change at Month 12 | 0.0 score on a scale | Standard Deviation 0 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Behavior: Baseline | 0.4 score on a scale | Standard Deviation 0.6 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Behavior: Change at Month 6 | -0.1 score on a scale | Standard Deviation 0.5 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Behavior: Change at Month 12 | -0.2 score on a scale | Standard Deviation 0.4 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Gelastic Cataplexy: Baseline | 0.4 score on a scale | Standard Deviation 0.8 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Gelastic Cataplexy: Change at Month 6 | 0.3 score on a scale | Standard Deviation 0.6 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Gelastic Cataplexy: Change at Month 12 | 0.3 score on a scale | Standard Deviation 0.6 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hyperreflexia: Baseline | 1.1 score on a scale | Standard Deviation 0.9 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hyperreflexia: Change at Month 6 | 0.2 score on a scale | Standard Deviation 0.6 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Hyperreflexia: Change at Month 12 | 0.1 score on a scale | Standard Deviation 0.5 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Incontinence: Baseline | 0.8 score on a scale | Standard Deviation 0.9 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Incontinence: Change at Month 6 | 0.1 score on a scale | Standard Deviation 0.5 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Incontinence: Change at Month 12 | 0.1 score on a scale | Standard Deviation 0.9 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Narcolepsy (NARCO): Baseline | 0.3 score on a scale | Standard Deviation 0.7 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Narcolepsy (NARCO): Change at Month 6 | -0.1 score on a scale | Standard Deviation 0.3 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Narcolepsy (NARCO): Change at Month 12 | -0.1 score on a scale | Standard Deviation 0.3 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Psychiatric: Baseline | 0.1 score on a scale | Standard Deviation 0.5 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Psychiatric: Change at Month 6 | 0.1 score on a scale | Standard Deviation 0.6 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Psychiatric: Change at Month 12 | 0.0 score on a scale | Standard Deviation 0.4 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Respiratory: Baseline | 0.0 score on a scale | Standard Deviation 0 |
| Placebo (12-month Double-blind Phase) | Changes From Baseline in Each Individual Domain of the NPCCSS | Respiratory: Change at Month 6 | 0.1 score on a scale | Standard Deviation 0.3 |
Secondary
Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y)
The EQ-5D-Y descriptive system includes 5 descriptive items: Mobility, self-care, doing usual activities, having pain or discomfort, and feeling anxiety or depressed. Each dimension has 3 levels: No problems, some problems, and a lot of problems. The change in the 5 individual items of the EQ-5D-Y per participant was explored by using the pareto principle at 6 and 12 months to show the number (%) of participants who felt: * Better (better on at least one dimension and no worse in any other dimension), * Worse (worse in at least one dimension, and no better in any other dimension)
Time frame: Baseline to 6 and 12 months
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication. Here, Overall Number of Participants Analyzed is the number of participants with data for the outcome measure and Number analyzed signifies number of participants evaluated at specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y) | Better: Change at Month 6 | 16.7 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y) | Worse: Change at Month 6 | 40.0 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y) | Better: Change at Month 12 | 25.9 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y) | Worse: Change at Month 12 | 44.4 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y) | Worse: Change at Month 12 | 20.0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y) | Better: Change at Month 6 | 26.7 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y) | Better: Change at Month 12 | 40.0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y) | Worse: Change at Month 6 | 46.7 percentage of participants |
Comparison: Percentage of participants with change from baseline at Month 6 in Quality of Life (EQ-5D-Y) being 'Better'p-value: 0.6951Chi-squared Test
Comparison: Percentage of participants with change from baseline at Month 6 in Quality of Life (EQ-5D-Y) being 'Worse'p-value: 0.7542Chi-squared Test
Comparison: Percentage of participants with change from baseline at Month 12 in Quality of Life (EQ-5D-Y) being 'Better'p-value: 0.488Chi-squared Test
Comparison: Percentage of participants with change from baseline at Month 12 in Quality of Life (EQ-5D-Y) being 'Worse'p-value: 0.1804Chi-squared Test
Secondary
Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I)
The CGI-I is a 7-point scale that rates total improvement of participant's condition. The clinician rates the participants from 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, or 7=Very much worse. Scores thus range from 1-7 with lower scores indicating greater improvement.
Time frame: Months 6 and 12
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication. Here, Overall Number of Participants Analyzed is the number of participants with data for the outcome measure and Number analyzed signifies number of participants evaluated at specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Very Much Worse | 3.7 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Much Improved | 3.7 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Very Much Improved | 3.4 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: No Change | 51.9 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Much Improved | 0 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Very Much Improved | 0 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Minimally Improved | 24.1 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Minimally Worse | 14.8 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: No Change | 37.9 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Very Much Worse | 0 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Minimally Worse | 27.6 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Much Worse | 7.4 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Much Worse | 6.9 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Minimally Improved | 18.5 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Much Worse | 16.7 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Very Much Worse | 0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Much Improved | 6.7 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Minimally Improved | 33.3 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: No Change | 20.0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Minimally Worse | 13.3 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Much Worse | 26.7 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Very Much Worse | 0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Very Much Improved | 0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Much Improved | 0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Minimally Improved | 25.0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: No Change | 25.0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 6: Minimally Worse | 33.3 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I) | Month 12: Very Much Improved | 0 percentage of participants |
Secondary
Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S)
The CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment. A rating of 1 is considered normal, or with the least severe symptoms, a rating of 7 is extremely ill, or the worst symptoms. Scores thus range from 1-7 with lower scores indicating less severe disease.
Time frame: Months 6 and 12
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication. Here, Overall Number of Participants Analyzed is the number of participants with data for the outcome measure and Number analyzed signifies number of participants evaluated at specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Normal, not ill at all | 0 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Borderline ill | 10.3 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Mildly ill | 27.6 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Moderately ill | 10.3 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Markedly ill | 31.0 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Severely ill | 20.7 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Most extremely ill participants | 0 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Normal, not ill at all | 0 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Borderline ill | 7.4 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Mildly ill | 29.6 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Moderately ill | 11.1 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Markedly ill | 29.6 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Severely ill | 22.2 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Most extremely ill participants | 0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Moderately ill | 33.3 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Normal, not ill at all | 0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Normal, not ill at all | 0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Borderline ill | 14.3 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Severely ill | 26.7 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Mildly ill | 28.6 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Borderline ill | 6.7 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Moderately ill | 35.7 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Markedly ill | 6.7 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Markedly ill | 0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Mildly ill | 26.7 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Severely ill | 14.3 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 12: Most extremely ill participants | 0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S) | Month 6: Most extremely ill participants | 7.1 percentage of participants |
Secondary
Percentage of Participants With Worsening
Worsening was defined as participants that have reached the predefined MCID of 2 points on their 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment.
Time frame: Months 6 and 12
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants With Worsening | Worsening at Month 6 | 35.3 percentage of participants |
| Arimoclomol (12-month Double-blind Phase) | Percentage of Participants With Worsening | Worsening at Month 12 | 44.1 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants With Worsening | Worsening at Month 6 | 50.0 percentage of participants |
| Placebo (12-month Double-blind Phase) | Percentage of Participants With Worsening | Worsening at Month 12 | 43.8 percentage of participants |
Comparison: Percentage of participants worsening at Month 6p-value: 0.3662Fisher's Exact Test
Comparison: Percentage of participants worsening at Month 12p-value: 1Fisher's Exact Test
Secondary
Percentage of Responders in 5-domain NPCCSS - Defined as Participants Where the 5-domain NPCCSS Score Remains Stable or Improves as Compared to Baseline
NPC disease severity was assessed based on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. Stable was defined as a participant's total score for the 5 domains being the same at month 12 as at baseline. Improvement was defined as a participant's total score at month 12 being lower than at baseline.
Time frame: Baseline to Month 12
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Percentage of Responders in 5-domain NPCCSS - Defined as Participants Where the 5-domain NPCCSS Score Remains Stable or Improves as Compared to Baseline | 50.0 percentage of responders |
| Placebo (12-month Double-blind Phase) | Percentage of Responders in 5-domain NPCCSS - Defined as Participants Where the 5-domain NPCCSS Score Remains Stable or Improves as Compared to Baseline | 37.5 percentage of responders |
p-value: 0.5456Chi-squared Test
Secondary
Percentage of Responders in Clinical Global Impression Scale of Improvement (CGI-I) - Defined as Percentage of Participants Where the CGI-I Score Remains Stable or Shows Improvement (This Outcome Measure Was Considered Co-primary by the FDA)
The CGI-I is a 7-point scale that rates total improvement of participant's condition. The clinician rates the participants from 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, or 7=Very much worse. Scores thus range from 1-7 with lower scores indicating greater improvement. Responders were the participants with a score of 1 or 2 at Month 12.
Time frame: Month 12
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Percentage of Responders in Clinical Global Impression Scale of Improvement (CGI-I) - Defined as Percentage of Participants Where the CGI-I Score Remains Stable or Shows Improvement (This Outcome Measure Was Considered Co-primary by the FDA) | 58.8 percentage of responders |
| Placebo (12-month Double-blind Phase) | Percentage of Responders in Clinical Global Impression Scale of Improvement (CGI-I) - Defined as Percentage of Participants Where the CGI-I Score Remains Stable or Shows Improvement (This Outcome Measure Was Considered Co-primary by the FDA) | 56.3 percentage of responders |
p-value: 1Chi-squared Test
Secondary
Time to Worsening
Time to worsening was defined as the time until the participant reached the predefined minimal clinically important difference (MCID) of 2 points compared to baseline on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. The values reported per group are the 25th percentile Kaplan-Meier estimates and 95% confidence interval.
Time frame: Baseline to Month 12
Population: FAS included those participants who were randomized and who had received at least one dose of randomized treatment medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arimoclomol (12-month Double-blind Phase) | Time to Worsening | 5.2 months |
| Placebo (12-month Double-blind Phase) | Time to Worsening | 5.5 months |
Comparison: Log-rank test had been stratified by miglustat use.p-value: 0.8021Log-Rank Test